title: Phosphorylation at tyrosine 262 promotes GADD34 protein turnover.
abstract: In mammalian cells, metabolic and environmental stress increases the phosphorylation of the eukaryotic translational initiation factor, eIF2α, and attenuates global protein synthesis. Subsequent transcriptional activation of GADD34 assembles an eIF2α phosphatase that feeds back to restore mRNA translation. Active proteasomal degradation of GADD34 protein then reestablishes the sensitivity of cells to subsequent bouts of stress. Mass spectrometry established GADD34 phosphorylation on multiple serines, threonines, and tyrosines. Phosphorylation at tyrosine 262 enhanced the rate of the GADD34 protein turnover. Substrate-trapping studies identified TC-PTP (PTPN2) as a potential GADD34 phosphatase, recognizing phosphotyrosine 262. Reduced GADD34 protein levels in TC-PTP-null MEFs following ER stress emphasized the importance of TC-PTP in determining the cellular levels of GADD34 protein. The susceptibility of TC-PTP-null MEFs to ER stress-induced apoptosis was significantly ameliorated by ectopic expression of GADD34. The data suggested that GADD34 phosphorylation on tyrosine 262 modulates endoplasmic reticulum stress signaling and cell fate.
authors.affiliation: From the Signature Research Programs in Cardiovascular and Metabolic Disorders and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Krishna
authors.initials: K
authors.lastname: Jeyaraman
authors.forename: Permeen
authors.initials: P
authors.lastname: Yusoff
authors.forename: Shirish
authors.initials: S
authors.lastname: Shenolikar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D014443:Tyrosine; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516653:Ptpn2 protein, mouse
keywords: Apoptosis; GADD34; Phosphotyrosine; Protein Turnover; Stress; Tyrosine Protein Phosphatase (Tyrosine Phosphatase)